This invention relates to a series of cinnamic acid derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature, 346 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A. ibid].
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al J. Exp. Med. 164, 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al J. Immunol. 157, 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different beta chains xcex21 and xcex27 [Sonnenberg, A. ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. et al. J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like xcex14xcex21, binds to VCAM-1 and fibronectin. In addition, xcex14xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al, PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognised by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst xcex14xcex27 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A. et al, PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of xcex14 integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on a integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1) 
wherein
Het is a heteroaromatic group;
R1, R2 and R3 which may be the same or different is each an atom or group xe2x80x94L2(Alk2)tL3(R7)u in which L2 and L3 which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2 or 3, Alk2 is an aliphatic or heteroaliphatic chain and R7 is a hydrogen or halogen atom or a group selected from alkyl, xe2x80x94OR8 [where R8 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94SR8, xe2x80x94NR8R9 [where R9 is as just defined for R8 and may be the same or different], xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94OCO2R8, xe2x80x94CONR8R9, xe2x80x94OCONR8R9, xe2x80x94CSNR8R9, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94N(R8)COR9, xe2x80x94N(R8)CSR9, xe2x80x94SO2N(R8)(R9), xe2x80x94N(R8)SO2R9, xe2x80x94N(R8)CON(R9)(R10), [where R10 is a hydrogen atom or an optionally substituted alkyl group] xe2x80x94N(R8)CSN(R9)(R10) or xe2x80x94N(R8)SO2N(R9)(R10);
Alk1 is an optionally substituted aliphatic or heteroaliphatic chain;
L1 is a covalent bond or a linker atom or group;
R4 and R5, which may be the same or different, is each a hydrogen or halogen atom or an alkyl, alkoxy, hydroxy or nitro group;
R6 and R6a, which may be the same or different, is each an atom or group xe2x80x94L2(Alk2)tL3R11 in which L2, L3, Alk2 and t are as previously defined and R11 is a hydrogen or halogen atom or an xe2x80x94OR8, xe2x80x94NR8R9, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94CONR8R9, xe2x80x94COR8, xe2x80x94N(R8)COR9, xe2x80x94N(R8)CSR9, xe2x80x94SO2N(R8)(R9), xe2x80x94N(R8)SO2R8, xe2x80x94N(R8)CON(R9)(R10), xe2x80x94N(R8)CSN(R9)(R10), xe2x80x94N(R8)SO2N(R9)(R10), or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
r is zero or the integer 1;
R is a carboxylic acid (xe2x80x94CO2H) or a derivative thereof;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) exist as geometric isomers (E or Z isomers). The compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such geometric isomers, enantiomers, diasteromers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds of formula (1), derivatives of the carboxylic acid group R include carboxylic acid esters and amides. Particular esters and amides include xe2x80x94CO2Alk5 and xe2x80x94CONR8R9 groups as described herein.
In general, the substituents R1, R2 and R3 in compounds of the invention may be positioned on any available carbon atom, or, when present, nitrogen atom in the heteroaromatic group represented by Het.
When in the compounds of formula (1) L1, L2 and/or L3 is present as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R12)xe2x80x94 [where R12 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94CON(R12), xe2x80x94OC(O)N(R12), xe2x80x94CSN(R12)xe2x80x94, xe2x80x94N(R12)COxe2x80x94, xe2x80x94N(R12)C(O)Oxe2x80x94, xe2x80x94N(R12)CSxe2x80x94, xe2x80x94S(O)2N(R12)xe2x80x94, xe2x80x94N(R12)S(O)2xe2x80x94, xe2x80x94N(R12)CON(R12)xe2x80x94, xe2x80x94N(R12)CSN(R12), or xe2x80x94N(R12)SO2N(R12)xe2x80x94 groups. Where the linker group contains two R12 substituents, these may be the same or different.
When R4, R5, R7, R8, R9, R10 and/or R12 in the compounds of formula (1) is an alkyl group it may be a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C1-6alkoxy e.g. methoxy or ethoxy groups.
Alkoxy groups represented by R4 and/or R5 in compounds of formula (1) include C1-6alkoxy groups such as methoxy or ethoxy groups. Halogen atoms represented by R4 and/or R5 include fluorine, chlorine, bromine, or iodine atoms.
When Alk1 in compounds of formula (1) is an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched chain C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl chains.
Heteroaliphatic chains represented by Alk1 include the aliphatic chains just described but with each chain additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is as defined above for L1 when L1 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic chain, or may be positioned at its terminal carbon atom to connect the chain to an adjoining atom or group.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3)CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94, or xe2x80x94(CH2)2CCxe2x80x94 chains. Where appropriate each of said chains may be optionally interrupted by one or two atoms and/or groups L4 to form an optionally substituted heteroaliphatic chain. Particular examples include optionally substituted xe2x80x94L4CH2xe2x80x94, xe2x80x94CH2L4CH2xe2x80x94, xe2x80x94L4(CH2)2xe2x80x94, xe2x80x94CH2L4(CH2)2xe2x80x94, xe2x80x94(CH2)2L4CH2xe2x80x94, xe2x80x94L4(CH2)3xe2x80x94 and xe2x80x94(CH2)2L4(CH2)2xe2x80x94 chains. The substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR13 and xe2x80x94N(R13)2 groups where R13 is an optionally substituted straight or branched alkyl group as defined above for R12. Where two R13 groups are present these may be the same or different.
Particular examples of substituted chains represented by Alk1 include those specific chains just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example chains of the type xe2x80x94CH(CF3)xe2x80x94, xe2x80x94C(CF3)2xe2x80x94 xe2x80x94CH2CH(CF3)xe2x80x94, xe2x80x94CH2C(CF3)2xe2x80x94, xe2x80x94CH(CF3)xe2x80x94 and xe2x80x94C(CF3)2CH2.
When Alk2 is present in the compounds of formulae (1) or (1a) as an aliphatic or heteroaliphatic chain it may be for example any of the above-mentioned C1-10aliphatic or heteroaliphatic chains described for Alk1.
Halogen atoms represented by R7 and/or R11 include fluorine, chlorine, bromine, or iodine atoms.
When R11 is present in compounds of formula (1) as an optionally substituted aliphatic or heteroaliphatic group it may be an aliphatic or heteroaliphatic group equivalent to the aliphatic or heteroaliphatic chain just described for Alk1. Each aliphatic or heteroaliphatic group may be optionally substituted by one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, xe2x80x94NH2 or substituted amino such as xe2x80x94NHR13 or xe2x80x94N(R13)2 as described above.
Optionally substituted cycloaliphatic groups represented by R11 include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C3-10cycloalkyl, e.g. C3-7cycloalkyl or C3-10 cycloalkenyl e.g. C3-7cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by R11 include the optionally substituted cycloaliphatic groups just described for R11 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups L4 where L4 is as defined above.
Particular examples of R11 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
The optional substituents which may be present on the R11 cycloaliphatic, or heterocycloaliphatic groups include one, two, three or more substituents each represented by R14 in which R14 is a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio amino or substituted amino group, e.g. a xe2x80x94NHR13 or xe2x80x94N(R13)2 group as described above. Additionally, when R11 is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group xe2x80x94(L5)p(Alk3)qR15 in which L5 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CON(R12)xe2x80x94, xe2x80x94CSN(R12)xe2x80x94, xe2x80x94SON(R12)xe2x80x94 or SO2N(R12)xe2x80x94; p is zero or an integer 1; Alk3 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1; and R15 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk3 include those chains described above for Alk1.
Optionally substituted cycloaliphatic or heterocycloaliphatic groups represented by R15 include those groups just described for R11. Optional substituents which may be present on these groups include one, two or three R14 substituents as just described.
Optionally substituted polycycloaliphatic groups represented by R15 include optionally substituted C7-10bi- or tricycloalkyl or C7-10bi- or tricycoalkenyl groups, for example norbornyl, norbornenyl or adamantyl groups. Polyheterocycloaliphatic groups include the polycycloalkyl groups just mentioned but with each group additionally containing one, two, three or four atoms or groups selected from those atoms and groups L4 described above. Optional substituents which may be present on the polycycloaliphatic or polyheterocycloaliphatic groups include those just described for R15 cycloaliphatic groups.
Optionally substituted aromatic or heteroaromatic groups represented by R15 included those aromatic and heteroaromatic groups generally and specifically described below for the group R11.
Optionally substituted aromatic groups represented by the group R11 in compounds of the invention include for example monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups, optionally substituted by one, two, three or more R16 atoms or groups as defined below.
Heteroaromatic groups represented by the group Het or R11 in the compounds of formula (1) include for example C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, Nxe2x80x94C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by R11 include one, two, three or more substituents, each selected from an atom or group R17 in which R17 is xe2x80x94R17a or xe2x80x94Alk4(R17a)m, where R17a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR18 [where R18 is an xe2x80x94Alk3(R17a)m, aryl or heteroaryl group], xe2x80x94CSR18, xe2x80x94SO3H, xe2x80x94SO2R18 xe2x80x94SO2NH2, xe2x80x94SO2NHR18 SO2N(R18)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR18, xe2x80x94CSNHR18, xe2x80x94CON[R18]2, xe2x80x94CSN(R18)2, xe2x80x94N(R12)SO2R18, xe2x80x94N(SO2R18)2, xe2x80x94NH(R12)SO2NH2, xe2x80x94N(R12)SO2NHR18, xe2x80x94N(R12)SO2N(R18)2, xe2x80x94N(R12)COR18, xe2x80x94N(R12)CON(R18)2, xe2x80x94N(R12)CSN(R18)2, xe2x80x94N(R12)CSR18, xe2x80x94N(R12)C(O)OR18, xe2x80x94SO2NHet1 [where xe2x80x94NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R12)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R12)SO2NHet1, xe2x80x94N(R12)CONHet1, xe2x80x94N(R12)CSNHet1, xe2x80x94SO2N(R12)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R12)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CON(R12)Het2, xe2x80x94CSN(R12)Het2, xe2x80x94N(R12)CON(R12)Het2, xe2x80x94N(R12)CSN(R12)Het2, aryl or heteroaryl group; Alk4 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R19)-groups [where R19 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R12 or R18 groups are present in one of the above substituents, the R12 or R18 groups may be the same or different.
When in the group xe2x80x94Alk4(R17a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R17a may be present on any suitable carbon atom in xe2x80x94Alk4. Where more than one R17a substituent is present these may be the same or different and may be present on the same or different atom in xe2x80x94Alk4. Clearly, when m is zero and no substituent R17a is present the alkylene, alkenylene or alkynylene chain represented by Alk4 becomes an alkyl, alkenyl or alkynyl group.
When R17a is a substituted amino group it may be for example a group xe2x80x94NHR18 [where R18 is as defined above] or a group xe2x80x94N(R18)2 wherein each R18 group is the same or different.
When R17a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R17a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR18 or a xe2x80x94SR18 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R17a include groups of formula xe2x80x94CO2Alk5 wherein Alk5 is a straight or branched, optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk5 group include R17a substituents described above.
When Alk4 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R12)xe2x80x94 groups.
Aryl or heteroaryl groups represented by the groups R17a or R18 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group R11. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When xe2x80x94NHet1 or xe2x80x94Het2 forms part of a substituent R17 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on xe2x80x94NHet1 or xe2x80x94Het2 include those R7 substituents described above.
Particularly useful atoms or groups represented by R17 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrrolyl, furyl, thiazolyl, or thienyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxy-propylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk5 [where Alk5 is as defined above], C1-6 alkanoyl e.g. acetyl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl. (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylamino-carbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonyl-amino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl, benzothio, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R17 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R17 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by R11.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
As noted above, the compounds of formula (1) may exist as geometric isomers. Thus, for example, one set of isomeric pairs of compounds of formula (1) is that wherein the R6 and R6a-containing groups are in a cis: 
or trans relationship: 
Although as explained previously the invention extends and relates to all geometric isomers of compounds of formla (1) certain of these isomers have particularly advantageous pharmacokinetic properties which makes them especially suitable for use in medicine. Thus, generally R6 and R6a are preferably in a trans relationship to each other [(B) above] in the compounds of formula (1).
In the compounds according to the invention the group Het is preferably a monocyclic heteroaromatic group. Particularly useful groups of this type are five- or six-membered heteroaromatic groups as described previously for Het, especially five- or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen atoms. Nitrogen-containing groups are especially useful, particularly pyridyl or pyrimidinyl groups.
In general in compounds of the invention each of R1, R2 and R3 is preferably a hydrogen atom or an optionally substituted alkyl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94NR8R9, xe2x80x94COR8, xe2x80x94CO2R8, xe2x80x94NO2 or xe2x80x94CN group as defined herein.
In one preferred grop of comppounds of formula (1) R6a is a hydrogen atom.
A particularly useful group of compounds according to the invention has the formula (2): 
wherein R1 and R2, which may be the same or different is each an atom or group xe2x80x94L2(Alk2)tL3(R7)u in which L2, Alk2, t, L3, R7 and u are as defined for formula (1) provided that R1 and R2 are not both hydrogen atoms;
Alk1, r, L1, R4, R5 and R are as defined for formula (1);
R6 is an atom or group xe2x80x94L2(Alk2)tL3R11 in which L2, L3, Alk2 and t are as previously defined and R11 is a hydrogen or halogen atom or an xe2x80x94OR8, xe2x80x94NR8R9, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94CONR8R9, xe2x80x94COR8, xe2x80x94N(R8)COR9, xe2x80x94N(R8)CSR9, xe2x80x94SO2N(R8)(R9), xe2x80x94N(R8)SO2R8, xe2x80x94N(R8)CON(R9)(R10), xe2x80x94N(R8)CSN(R9)(R10), xe2x80x94N(R8)SO2N(R9)(R10), or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
In the compounds of formula (2) the R6 and pyridyl-containing substituents preferably have a cis relationship as shown in (B) above.
R1 and R2 in compounds of formula (2) is each preferably as described above other than a hydrogen atom. Particularly useful R1 and R2 substituents in compounds of the invention include halogen atoms, especially fluorine or chlorine atoms, methyl, ethyl, methoxy, ethoxy, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94COCH3, xe2x80x94SCH3, xe2x80x94CO2H or xe2x80x94CO2CH3 groups.
R in the compounds of formulae (1) and (2) is preferably a xe2x80x94CO2H group.
When present, the aliphatic chain represented by Alk1 in compounds of formulae (1) and (2) is preferably a xe2x80x94CH2xe2x80x94 chain.
In general in compounds of formulae (1) and (2) xe2x80x94(Alk1)rL1xe2x80x94 is preferably xe2x80x94CH2Oxe2x80x94 or xe2x80x94CON(R12)xe2x80x94, and is especially a xe2x80x94CONHxe2x80x94 group. The xe2x80x94(Alk1)rL1xe2x80x94 group is preferably attached to the 4-position of the phenyl ring containing the R4 and R5 substituents.
Particularly useful classes of compounds according to the invention are those wherein R6 is a xe2x80x94L2R11 or xe2x80x94L2Alk2R11 atom or group. In these classes, L2 when present as a linker atom or group may especially be a xe2x80x94NHCOxe2x80x94, xe2x80x94NHCSxe2x80x94 or xe2x80x94NHSO2xe2x80x94 group. Alk2 when present may especially be a C1-4alkylene chain. R11 may especially be a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein. Particularly useful R11 groups include optionally substitued C5-7cycloaliphatic, especially optionally substituted pyrrolidinyl, optionally substituted C5-7heterocycloaliphatic, especially optionally substituted pyrrolidinyl or thiazolidinyl, optionally substituted phenyl and optionally substituted C5-7heteroaromatic, especially optionally substituted pyridinyl groups. Optional substituents on these groups include in particular R17 atoms or groups where the group is an aromatic or heteroaromatic group and xe2x80x94(L5)p(Alk3)qR15 groups as described earlier where the group is a nitrogen-containing heterocyclo-aliphatic group such as a pyrrolidinyl or thiazolidinyl group. Particularly useful (L5)p(Alk3)qR15 groups include xe2x80x94L5CH2R15 groups in which R15 is a hydrogen atom or an optionally substituted aromatic, particularly optionally substituted phenyl, or optionally substituted heteroaromatic, particularly optionally substituted pyridyl group as defined herein. In these groups L5 may be as defined above, and is especially a xe2x80x94C(O)xe2x80x94 group.
Particularly useful compounds according to the invention include:
N-Acetyl-D-thioproline-4-[(3,5-dichloroisonicotinoyl)amino]-Z-didehydrophenylalanine;
N-Acetyl-D-thioproline-4-[(3,5-dichloroisonicotinoyl)amino]-E-didehydrophenylalanine;
N-Trimethylacetyl-4-[(3,5-dichloroisonicotinoyl)amino]-Z-didehydrophanylalanine;
N-Trimethylacetyl-4-[(3,5-dichloroisonicotinoyl)amino]-E-didehydrophenylalanine;
N-(2-Chloronicotinoyl)4-[(3,5-dichloroisonicotinoyl)amino]-Z-didehydrophenylalanine;
(Z)-3-{4-[(3,5-Dichloro-4-pyridinyl)methoxy]phenyl}-2-[(2,6-dimethoxybenzoyl)amino]-2-propenoic acid;
N-(2-Chloronicotinoyl)-4-[(3,5-dichloroisonicotinoyl)amino]-E-didehydrophenylalanine;
and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of xcex14 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter. In particular compounds of the invention, such as the compounds of formula (1a) herein, are advantageously selective xcex14xcex21 inhibitors.
The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1-R6 and R6a, L1, Alk1 and r when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formulae (1a) and (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a xe2x80x94CO2H group may be obtained by hydrolysis of an ester of formula (3): 
where Ra is an alkyl group, for example a C1-6alkyl group as described above.
The hydrolysis may be performed using either an acid or a base depending on the nature of Ra, for example an organic acid such as trifluoracetic acid or an inorganic base such as lithium or potassium hydroxide optionally in an aqueous organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
Esters of formula (3) and, in general, esters of formula (1) in which R is a xe2x80x94CO2Alk5 group may be prepared by reaction of an aldehyde or ketone of formula (4): 
with a phosphonate (Alk6O)2P(O)CH(R6)CO2Alk5, where Alk6 is a C1-6alkyl group optionally substituted by one or more fluorine atoms, in the presence of a base.
Suitable bases include organometallic bases, for example an organolithium compound such as n-butyllithium or lithium diisopropylamide, hydrides such as sodium or potassium hydride, alkoxides, such as sodium alkoxides, e.g. sodium methoxide, and cyclic amines, for example 1,8-diazabicyclo[5.4.0]undec-7-ene.
The reaction may be performed in a suitable solvent, for example a polar aprotic solvent such as an amide, e.g. N,N-dimethylformamide; or a non-polar solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon, e.g. dichloromethane. Preferably the react ion is carried out at a low temperature for example from around xe2x88x9278xc2x0 C. to around ambient temperature.
Intermediate phosphonates of formula (Alk6O)2P(O)CH(R6)CO2Alk5 are either known compounds or may be obtained by reaction of a halide HalCH(R6)CO2Alk5 [where Hal is a halogen atom such as a chlorine or bromine atom] with a phosphite P(OAlk6)3. The halides HalCH(R6)CO2Alk5 are either known compounds or may be prepared by manipulation of known compounds by the standard substitution, oxidation, reduction and/or cleavage reactions described hereinafter. In general the reaction with the phosphite P(OAlk6)3 may be carried out at any stage in the synthesis of the desired phosphonate (Alk6O)2P(O)CH(R6)CO2Alk5.
Intermediate aldehydes of formula (4) are either known compounds or may be prepared by simple chemical manipulation of known compounds.
Thus, for example, the aldehydes [where R6a is a hydrogen atom] may be obtained by oxidation of the corresponding alcohols [in which xe2x80x94COR6a is replaced by a xe2x80x94CHOH group] using an oxidising agent such as manganese (IV) oxide in a solvent such as dichloromethane.
Intermediate ketones of formula (4) [where R6a is other than a hydrogen atom] may also be obtained by oxidation of the corresponding alcohol of formula (4), using for example manganese (IV) oxide in a solvent such as dichlromethane, or by reaction of a corresponding halide [in which xe2x80x94COR6a has been replaced by a halogen atom such as a bromine or chlorine atom] by halogen-metal exchange with a base such as n-butyllithium followed by reaction with a nitrile R6aCN, an acid chloride R6aCOCl or an ester R6aCO2Ra, in a solvent such as tetrahydrofuran, at a low temperature e.g. around xe2x88x9270xc2x0 C. and subsequent treatment with an acid such as hydrochloric acid at around ambient temperature.
In another process, esters or amides of formula (1), for example where R is a carboxylic acid ester or amide, and in which R6 or R6a is a hydrogen atom, may be prepared by coupling an organpalladium compound derived from an intermediate of formula (5): 
[in which X1 is a halogen atom such as an iodine atom or is a trifluoromethylsulphonyloxy group] and a palladium salt with an ester or amide R6aCHCHR or CH2C(R6)R where R is as just defined in the presence of a base.
Suitable palladium salts include palladium acetate or palladium chloride. Where palladium acetate is used the reaction for example may be carried out under phase-transfer conditions in the presence of tetra-n-butylammonium bromide and an alkali-metal base such as sodium bicarbonate in dimethylformamide. In another example, the reaction may be performed using palladium acetate or palladium chloride and a phosphine, for example a triarylphosphine such as triphenylphosphine, and a base such as triethylamine, at for example an elevated temperature and pressure.
Where desired, the starting materials in the above general coupling reaction may be varied. The reaction may thus be performed using an ester or amide of formula (1) in which R is a carboxylic acid ester or amide and R6 and R6a is each a hydrogen atom with a reagent R6bX1 in which R6b is an aromatic or heteroaromatic group and X1 is as defined above. Similarly the reaction may be used to generate intermediates to the final compounds described herein, for example intermediate esters of formula (3) by using the appropriate alkene ester and a reagent R6bX1.
Where necessary, the intermediate aldehydes and ketones of formula (4) and the corresponding alcohols and halides described above, as well as the intermediates of formula (5) and the esters or amides R6aCHCHR or CH2C(R6)R may be obtained from simpler aromatic or heteroaromatic compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to modify the compounds of formula (1) and the esters (3) where appropriate functional groups exist in these compounds and to generate suitable phosphonates (Alk6O)2P(O)CH(R6)CO2Alk5 for example to obtain desired groups xe2x80x94CH(R6)CO2Alk5 therein.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a xe2x80x94L1H, xe2x80x94L2H, or xe2x80x94L3H group (where L1, L2 and L3 (is each a linker atom or group) may be treated with an alkylating agent: 
R11L3(Alk2)tX2 or R11X2 in which X2 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
In another example, compounds containing a xe2x80x94L1H, xe2x80x94L2H or xe2x80x94L3H group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X2 is replaced by a xe2x80x94C(O)X3, C(S)X3, xe2x80x94N(R8)COX3 or xe2x80x94N(R8)C(S)X3 group in which X3 is a leaving atom or group as described for X2. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature. Alternatively, the acylation or thioacylation may be carried out under the same conditions with an acid or thioacid (for example one of the alkylating agents described above in which X2 is replaced by a xe2x80x94CO2H or xe2x80x94COSH group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole.
Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction
In a further example compounds may be obtained by sulphonylation of a compound containing an xe2x80x94OH group by reaction with one of the above alkylating agents but in which X2 is replaced by a xe2x80x94S(O)Hal or xe2x80x94SO2Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a xe2x80x94L1H, xe2x80x94L2H or xe2x80x94L3H group as defined above may be coupled with one of the alkylation agents just described but in which X is preplaced by an xe2x80x94OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
In a further example, ester groups xe2x80x94CO2R8 or xe2x80x94CO2Alk5 in the compounds may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R8 or Alk5. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a second example, xe2x80x94OR8 or xe2x80x94OR18 groups [where R8 or R18 each represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R18 group (where R18 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [xe2x80x94CO2Alk5 or CO2R8] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in the compounds may be converted to a corresponding xe2x80x94OR8 group by coupling with a reagent R8OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, dilsopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid in a solvent such as ethanol at an elevated temperature
Reduction, for example using a metal and reaction conditions as just described, may also be used to obtain a compound in which L2 is a xe2x80x94NHCOxe2x80x94 group from the corresponding oxazolone in which L is 
The oxazolone may be prepared by reaction of an appropriate amino acid or a reactive derivative thereof and a ketone in the presence of a catalyst, for example a lead salt such as lead acetale, in a solvent such as tetrahydrofuran at an elevated temperature.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyidisulphide as the electrophile.
In a further example, compounds in which R6a is an aromatic group may be prepared by reaction of a corresponding compound in which R6a is a halogen atom such as a bromine atom with a boronic acid R6aB(OH)2 [where R6a is an aromatic group] in the presence of a complex metal catalyst. Suitable catalysts include heavy metal catalysts, for example palladium catalysts, such as tetrakis(triphenylphosphine)palladium. The reaction may be performed in an inert organic solvent, for example an ether such as dimethoxyethane or dioxane, in the presence of a base, e.g. an alkali carbonate such as sodium carbonate, at an elevated temperature, e.g. the reflux temperature.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1, L2 or L3 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suit able solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystalliation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. All temperatures are in xc2x0C. The following abbreviations are used:
DMFxe2x80x94dimethylformamide;
DMSOxe2x80x94dimethylsulphoxide;
HOBTxe2x80x941-hydroxybenzotriazole;
THFxe2x80x94tetrahydrofuran;
NMMxe2x80x94N-methylmorpholine;
EtOAcxe2x80x94ethyl acetate;
MeOHxe2x80x94methanol;
LDAxe2x80x94lithium diisopropylamide
Arxe2x80x94aryl;
pyxe2x80x94pyridine;
Mexe2x80x94methyl;
Buxe2x80x94butyl;
DBUxe2x80x941,8-diazabicyclo[5.4.0]undec-7-ene;
DMExe2x80x94dimethoxyethane
All NMR""s were obtained at 300 mHz.